Prozac-induced brain changes linked to unstable behavior

Clinicians sometimes choose medications based on unique characteristics like side effect profiles. An example of this is choosing a drug with a side effect of sedation and giving it at night for someone who has difficulty with sleep.

Fluoxetine, also known by the brand-name Prozac, has often been called an ‘activating’ drug. Due to this reputation, some clinicians will consider it for patients with low energy or schedule it for the morning, and others might avoid it in patients who are highly anxious.

Drugs in the same class as fluoxetine, also known as SSRIs, are sometimes also avoided due to concerns of causing a side effect known as a manic switch – which is when someone goes from having symptoms of depression and low energy to having increased energy, decreased need for sleep and elevated mood.

A new research study from Japan has demonstrated that chronic treatment of adult mice with fluoxetine (Prozac) causes changes to brain cells that were associated with day-to-day fluctuations in activity levels as well as anxiety-related behaviors. The study was published in the journal Molecular Brain.

Dr. Katsunori Kobayashi is the lead author and he told me that this work is the first to link a destabilization in behavior to SSRI-induced neuronal plasticity. Plasticity is the ability of the brain cell or neuron to change its connections and interactions with other neurons. Previous research has associated SSRI-induced plasticity with antidepressant effects.

The researchers gave fluoxetine at a higher and lower dose to mice for 4 weeks. At first they noticed a slight decrease in activity at both doses. After 2 weeks of treatment, the mice at the higher dose started to show “marked day-to-day fluctuation of activity levels that was accompanied by occasional switching from hypoactivity to hyperactivity and vice-versa.” This destabilized activity was accompanied by increased anxiety-related behaviors and could be observed up to 4 weeks after withdrawal from fluoxetine.

At a cellular level, the authors noted that the behavioral changes, including anxiety-related behaviors, were associated with fluoxetine-induced adaptations in hippocampal granule cells, which are specialized cells found in the brain.

They previously showed that fluoxetine could reverse the state of maturation of hippocampal granule cells in adult mice. This fluoxetine-induced plasticity or ‘dematuration’ causes the cell to revert back to a juvenile state where it is doesn’t work as well with other specialized cells. In this study, the authors noted that the behavioral and cellular effects persisted after fluoxetine was discontinued. Dr. Katsunori reported that “the dematuration can be observed 1 month after discontinuation, so it is not readily reversible.”

One of the obvious limitations to this study is the fact that what happens in mice doesn’t necessarily translate to humans. Another limitation is the supratherapeutic dosing used in the mice, 22mg/kg/day at the higher dose and even 14mg/kg/day at the lower dose. In a 150 pound human, this would equal taking up to 1500 mg of Prozac per day and most people don’t take more than 80 mg daily. It would also be considered quite a leap to extrapolate a manic switch from “marked day-to-day fluctuation of activity levels.”

Despite these limitations, this study could help shed some light on how these drugs affect our brains, and may provide a potential neurobiological basis for why Prozac may be ‘activating’.

Dr. Katsunori stated that clinicians should be careful about interpreting the behavioral effects of the drugs, but that their results suggest that “Prozac may cause destabilized behavior” at higher doses or “possibly in combination with other drugs that can effect metabolism of Prozac or enhance its central action.”